1. Field of the Invention
The present invention relates to a purified salt of xcex2-hydroxyethoxy acetic acid, which is a precursor of a purified 2-p-dioxanone.
The present invention relates to a manufacturing method of a purified salt of xcex2-hydroxyethoxy acetic acid, which is a precursor of a purified 2-p-dioxanone.
The present invention relates to a manufacturing method of a purified 2-p-dioxanone obtained from a purified salt of xcex2-hydroxyethoxy acetic acid.
The present invention relates to a method of manufacturing a purified 2-p-dioxanone in an industrially advantageous manner.
The present invention also relates to a purified 2-p-dioxanone having a function to produce a polyparadioxane having a high molecular weight and a narrow molecular weight distribution characterized by not having a carboxyl group at the molecule end, after a polymerization reaction.
The present invention relates to a purified 2-p-dioxanone having a function to produce a polyparadioxane having a high molecular weight and a narrow molecular weight distribution characterized by not detecting a peak in 8.1 ppm attributable to a proton of a carboxyl group by nuclear-magnetic-resonance spectrometry (NMR, measured at 25 xc2x0 C.).
2. Description of the Related Art
[Technical Background of a Salt of xcex2-hydroxyethoxy Acetic Acid]
It has conventionally been said to be a common sense by so-call those skilled in the art that purified salts of xcex2-hydroxyethoxy acetic acid are oily, not crystalline, and that a fusion peak-top temperature is not detected by differential scanning calorimetry (DSC). No literature describes melting points of salts of xcex2-hydroxyethoxy acetic acid.
[Investigation on Salts of xcex2-Hydroxyethoxy acetic acid by the Present Inventors]
The present inventors have thus conducted investigations eagerly and obtained a novel finding that in the course of purification of salts of xcex2-hydroxyethoxy acetic acid, they change from an oily state to crystalline and the fusion peak-top temperature gradually becomes measurable by differential scanning calorimetry (DSC).
According to the novel finding by the present inventors, the fusion peak-top temperature is preferably 205 to 208xc2x0 C., more preferably 206 to 207xc2x0 C., further preferably 206.5xc2x10.2xc2x0 C.
[Technical Background of 2-p-dioxanone]
2-p-Dioxanone is a compound useful as a raw material for a biodegradable and absorbable polymer used in a medicine etc.
[Investigation on 2-p-Dioxanone by the Present Inventors]
In the course of eager investigation on the technology for manufacturing a polydioxane having a narrow molecular weight distribution, the present inventors have obtained a finding that hydrochloric acid and acid chlorides among impurities present in 2-p-dioxanone inhibit manufacturing of a polydioxane having a narrow molecular weight distribution.
In other words, the present inventors have obtained a finding that hydrochloric acid and acid chlorides, if present in 2-p-dioxanone, would generate undesirable impurities due to their high reactivity, and the undesirable impurities involves such a critical problem that even if only a trace amount remains, they promotes ring-opening, cleavage, and degradation of 2-p-dioxanone.
The present inventors have found that if such ring-opening, cleavage, and degradation occur, undesirable impurities having a carboxyl group at ends are produced, which in turns inhibit a ring-opening polymerization reaction, suppress an increase in molecular weight, induce production of undesirable oligomers, and widen a molecular weight distribution as well.
According to the findings of the present inventors as described above, such an empirical rule has been obtained that a molecular weight distribution is wide when a large amount of carboxyl groups are present at molecular ends of a polymer, while a molecular weight distribution is narrow when no carboxyl group is present at molecular ends of a polymer, that is, an amount of carboxyl groups at molecular ends of a polymer is an index of molecular weight distribution.
It is deduced from the above described findings of the present inventors that removal of hydrochloric acid and acid chlorides from 2-p-dioxanone solves the problems of the prior art.
The present inventors have then found that it is quite difficult to remove hydrochloric acid and acid chlorides efficiently from 2-p-dioxanone by purification measures such as distillation and the like.
Then, the present inventors have found that it is quite easy to purify a salt of xcex2-hydroxyethoxy acetic acid, a precursor of 2-p-dioxanone, and reached to consider whether a purified 2-p-dioxanone, which has been purified and requires no further purification, might be readily obtained from a purified precursor, and thus preceded eager investigation.
[Prior Art for Process of Manufacturing 2-p-Dioxanone]
The following prior art can be mentioned with respect to processes of manufacturing 2-p-dioxanone.
(1) Process of Synthesis from 2,3-Dichloro-p-dioxanone
J. Am. Chem. Soc. Vol. 80, 604-608 (1958) discloses a process of manufacturing 2-p-dioxanone in which trans-2,3-dichloro-p-dioxane is reacted with an acid chloride represented by formula (3) to obtain 2-carboxy-3-chloro-p-dioxane (4) represented by the following formula (4), and then 2-carboxy-3-chloro-p-dioxane is subjected to heat treatment to obtain 2,3-dichloro-p-dioxanone. 
where R represents p-C6H4Cl, CH3, and H.
This manufacturing process has such a problem that hydrochloric acid and acid chlorides are produced as byproducts, however.
The byproducts, hydrochloric acid and acid chlorides, are highly reactive with an object, 2-p-dioxanone, to produce undesirable impurities. The undesirable impurities involve such a critical problem that even if only a trace amount remains, they promote ring-opening, cleavage, and degradation of 2-p-dioxanone.
When such ring-opening, cleavage, and degradation occur, undesirable impurities having a carboxyl group at ends are produced.
These undesirable impurities in turns inhibit a ring-opening polymerization reaction, suppress an increase in molecular weight, and induce production of undesirable oligomers, and widen a molecular weight distribution as well.
As described above, such an empirical rule has been obtained that a molecular weight distribution is wide when a large amount of carboxyl groups are present at molecular ends of a polymer, while a molecular weight distribution is narrow when no carboxyl group is present at molecular ends of a polymer, that is, an amount of carboxyl groups at molecular ends of a polymer is an index of molecular weight distribution.
In addition, the raw material, 2,3-dichloro-p-dioxanone, also generates hydrochloric acid and acid chlorides as byproducts in its manufacturing process and has problems similar to those described above.
In addition, 2,3-dichloro-p-dioxane, a raw material of this synthetic route, is generally synthesized by a reaction of dioxane with sulfuryl chloride, but each 2 equivalents of HCl and SO2 gases are generated, treatment of which gases is industrially problematic.
(2) Process of Synthesis from Diol Using Catalyst
There have been a great number of reports concerning a method in which diethylene glycol is subjected to a dehydrogenation reaction by heating to a high temperature using a corresponding quantity of a catalyst to obtain 2-p-dioxanone. For example, Japanese Patent Application Laid-Open No. 4-505321 discloses a method of manufacturing 2-p-dioxanone by a catalytic dehydrogenation reaction of dialkylene glycol comprising the step of contacting dialkylene glycol with an effective amount of a dehydrogenation catalyst containing catalytically effective amounts of copper compounds, zinc compounds, and co-catalyst compounds. The selectivity rates in the examples are 73.7 to 99%.
Japanese Patent Application Laid-Open No. 10-120675 describes a process of manufacturing 2-p-dioxanone in which diethylene glycols are contacted with a catalyst comprising copper on a carrier with acid strength (Ho) more than 1.5 and a total amount of acid points in the range of 0 to 2xc3x9710xe2x88x927 equivalent per square meters in the present of hydrogen at temperature in the range from 200 to 400xc2x0 C. The selectivity rates in the examples are 95 to 98%.
In addition, in Bull. Chem. Soc., Jpn., vol. 35, 986-(1962), Japanese Patent Application Laid-Open No. 58-99476, U.S. Pat. Nos. 2,807,629, 2,900,395, and 5,391,707, a method to obtain 2-p-dioxanone by a dehydrogenation reaction by heating at a high temperature and using a corresponding amount of a catalyst.
Although selectivity rates have been improved through investigation of catalysts for these manufacturing methods, however, these reactions are still conducted at high temperatures. Thus, in order to treat 2-p-dioxanone that is unstable to heat, a reaction must be conducted in an atmosphere of hydrogen or oxygen and the like so that special high-pressure gas equipments must be employed for manufacturing.
Therefore, special high-pressure gas equipments, considering safety and maintenance and facility management, must be large-scale ones, which is industrially and economically problematic.
(3) Synthesis by Reaction between Diol and Organic Acids
Japanese Patent Application Laid-Open No. 1-299279 describes a manufacturing process in which organic compounds containing at least 2 primary hydroxyl groups in the molecule are subjected to oxidative intramolecular dimerization of the 2 hydroxyl groups using organic acids in the presence of halogen compounds to produce lactone compounds. 2-p-Dioxanone, the object of the present invention, is included in a category of cyclic lactones. The reaction formula of this manufacturing process is shown by formula (5). 
Although this manufacturing process is effective means to obtain lactones, however, carboxylic acid produced in 2 equivalents as a byproduct is highly reactive with 2-p-dioxane and is industrially problematic, considering recovering the product and the like.
(4) Process of Manufacturing from Sodium xcex2-Hydroxyethoxy acetate
Japanese Patent Application Laid-Open No. 60-36785 discloses a process of manufacturing 2-p-dioxanone to be used as a raw material of synthetic absorbable sutures. This process uses inexpensive ethylene glycol and chloroacetic acid as raw materials and can be said an industrial manufacturing process in this respect. The embodiment of this manufacturing process is as follows.
Metal sodium is dissolved in a largely excessive amount of ethylene glycol to obtain glycolate, which is then reacted with choroacetic acid in a quantity of about 0.5 mol per 1 mol of sodium to obtain a sodium salt of hydroxy acid.
After reaction, excess ethylene glycol and reaction byproducts are removed by distillation and washing with acetone, and the sodium salt is converted into a free hydroxy acid by addition of hydrochloric acid. The formed sodium chloride is then removed by sedimentation with ethanol followed by filtration.
After that, a filtrate of the hydroxy acid is slowly heated to about 200xc2x0 C. preferably in the presence of MgCO3 to remove alcohol and water by distillation. Further heating under atmospheric pressure results in production of p-dioxanone, which is distilled off at a tower top temperature of about 200 to 220xc2x0 C. It is disclosed that the purity of the crude dioxanone product measured by gas chromatography is generally about 60-70% and its yield is about 50 to 70%.
The crude p-dioxanone is purified by redistillation to a purity of about 98% and finally by multi-step crystallization and/or distillation to a purity not lower than 99%.
(5) Problems of Synthetic Process Described in (4)
The synthetic process of (4) is certainly effective means for synthesis in order to solve the former technical problems.
However, the synthetic process of (4) has such a problem that 2-p-dioxanone obtained at first has a low purity, thus requires several times of purification. That is, considering industrial manufacturing, such complicated operations are problematic in terms of productivity indeed.
The present inventors conducted a follow-up study on the synthetic process (4). The results showed that remaining ethylene glycol as well as remaining glycolates or chloroacetic acid affected the cyclization reaction to reduce the yield. If ethylene glycol remains, it is difficult to separate by distillation due to its boiling point close to that of 2-p-dioxanone, and thus it is difficult to obtain a highly purified 2-p-dioxanone. In addition, 2-p-dioxanone tends to be cleaved by a reaction with the impurity to change to oligomers. If glycolate remains, when hydrochloric acid is added, the sodium salt is detached to produce ethylene glycol and a reaction the same as that described above occurs. If chloroacetic acid remains, it is reactive with the sodium salt of hydroxy acid and 2-p-dioxanone. As a result, production of the byproducts or cleavage of 2-p-dioxanone occurs during the neutralization/cyclization reaction after addition of hydrochloric acid. Although several times of purification is required in order to obtain highly purified and stable 2-p-dioxanone, an actual yield is only about 20 to 30%. This process thus cannot be said an excellent method.
(1) One of the objects of the present invention is to provide a purified 2-p-dioxanone having a function to produce polyparadioxane having a high molecular weight and a narrow molecular weight distribution characterized by not having a carboxyl group at molecular ends after a polymerization reaction.
(2) One of the objects of the present invention is to provide a purified 2-p-dioxanone having a function to produce polyparadioxane having a high molecular weight and a narrow molecular weight distribution characterized in that a peak at 8.1 ppm attributable to a proton of a carboxyl group by nuclear magnetic resonance spectrometry (NMR, measured at 25xc2x0 C.) is not detected after a polymerization reaction.
(3) One of the objects of the present invention is to provide a purified salt of xcex2-hydroxyethoxy acetic acid, a precursor of a purified 2-p-dioxanone, which can readily be derived to the purified 2-p-dioxanone described in (1) and (2).
(4) One of the objects of the present invention is to provide a process of manufacturing a purified salt of xcex2-hydroxyethoxy acetic acid, a precursor of a purified 2-p-dioxanone, which can readily be derived to the purified 2-p-dioxanone described in (1) and (2).
(5) One of the objects of the present invention is to provide a purified salt of xcex2-hydroxyethoxy acetic acid, a precursor of a purified 2-p-dioxanone, which can readily be derived to the purified 2-p-dioxanone.
(6) One of the objects of the present invention is to provide a process of manufacturing a purified salt of xcex2-hydroxyethoxy acetic acid, a precursor of a purified 2-p-dioxanone, which can readily be derived to the purified 2-p-dioxanone.
(7) One of the objects of the present invention is to provide a process of manufacturing a purified 2-p-dioxanone from a purified salt of xcex2-hydroxyethoxy acetic acid.
(8) One of the objects of the present invention is to provide a process of manufacturing a purified 2-p-dioxanone in an industrially advantageous manner.
(9) One of the objects of the present invention is to provide technology for manufacturing a highly purified 2-p-dioxanone that is suitable as a raw material for polymers having a high molecular weight and narrow molecular weight distribution and contains less impurities at a high yield, considering the problems of the prior art.
(10) One of the objects of the present invention is to provide a purified 2-p-dioxanone, which can produce biodegradable absorbable polymers to be used for drugs and the like and polymers with a high molecular weight and narrow molecular weight distribution that can be extremely suitably used for sutures for surgical operations.
The present inventors considered the problems in the above described xe2x80x9c(4) Synthesis from Sodium xcex2-Hydroxyethoxy acetatexe2x80x9d in the Prior Art and proceeded research eagerly.
As a result, the present inventors have obtained a novel finding that 2-p-dioxanone is highly reactive with organic acids, especially carboxylic acids or acid halides and substances having a hydroxyl group, especially diols such as ethylene glycol and diethylene glycol and therefore remaining of these substances affects to stability of 2-p-dioxanone, and removal of these impurities largely contributes to remarkable improvement of a reaction yield.
According to the process of manufacturing 2-p-dioxanone of the present invention, after purified sodium xcex2-hydroxyethoxy acetate is first isolated to obtain a precursor (intermediate) containing less impurities, a cyclization reaction is conducted followed by distillation once. As a result, a purified 2-p-dioxanone having a sufficient purity to be used for a monomer can be obtained.
The 2-p-dioxanone obtained by the manufacturing process according to the present invention is a monomer suitable for polymers that have a high molecular weight and a narrow molecular weight distribution required as raw materials of bioabsorbable materials.
The present invention is specified by the items described in [1] to [16] below.
[1] A purified salt of xcex2-hydroxyethoxy acetic acid which is characterized by detecting fusion peak-top temperature by differential scanning calorimetry (DSC) and which is represented by formula (1). 
xe2x80x83(wherein in formula (1), n=1-2, and if n=1, M is Na and/or K, and, if n=2, M is Ca and/or Mg.)
[2] The purified salt of xcex2-hydroxyethoxy acetic acid as described in [1], characterized in that the fusion peak-top temperature is 205 to 208xc2x0 C.
[3] The purified salt of xcex2-hydroxyethoxy acetic acid as described in [1], characterized in that the fusion peak-top temperature is 206 to 207xc2x0 C.
[4] The purified salt of xcex2-hydroxyethoxy acetic acid as described in [1], characterized in that the fusion peak-top temperature is 206.5xc2x0 C.
[5] A process of manufacturing a purified salt of xcex2-hydroxyethoxy acetic acid represented by the following formula (1), of which a fusion peak-top temperature is detected by differential scanning calorimetry (DSC), characterized in that the process comprises the steps of:
sedimenting a salt of xcex2-hydroxyethoxy acetic acid of formula (1), a fusion peak-top temperature of which is not detected by differential scanning calorimetry (DSC), with a poor solvent; and
washing a sedimented salt of xcex2-hydroxyethoxy acetic acid with the poor solvent, 
xe2x80x83(wherein in formula (1), n=1-2, and if n=1, M is Na and/or K, and, if n=2, M is Ca and/or Mg.)
[6] The process of manufacturing a purified salt of xcex2-hydroxyethoxy acetic acid as described in [5], characterized in that the fusion peak-top temperature of an obtained purified salt of xcex2-hydroxyethoxy acetic acid is 205 to 208xc2x0 C.
[7] The process of manufacturing a purified salt of xcex2-hydroxyethoxy acetic acid as described in [5], characterized in that the fusion peak-top temperature of an obtained purified salt of xcex2-hydroxyethoxy acetic acid is 206 to 207xc2x0 C.
[8] The process of manufacturing a purified salt of xcex2-hydroxyethoxy acetic acid according as described in [5], characterized in that the fusion peak-top temperature of an obtained purified salt of xcex2-hydroxyethoxy acetic acid is 206.5xc2x0 C.
[9] A purified salt of xcex2-hydroxyethoxy acetic acid represented by the following formula (1) obtained by the production process according to any one of the manufacturing methods described in [5] to [8], 
xe2x80x83(wherein in formula (1), n=1-2, and if n=1, M is Na and/or K, and, if n=2, M is Ca and/or Mg.)
[10] A process of manufacturing a purified 2-p-dioxanone represented by the following formula (2), characterized in that a purified salt of xcex2-hydroxyethoxy acetic acid represented by the following formula (1), a fusion peak-top temperature of which is detected by differential scanning calorimetry (DSC), is reacted with an inorganic acid, whereby a neutralization reaction and a cyclization reaction are performed in the same system, 
xe2x80x83(wherein in formula (1), n=1-2, and if n=1, M is Na and/or K, and, if n=2, M is Ca and/or Mg.) 
[11] The process of manufacturing a purified 2-p-dioxanone as described in [10], characterized in that the fusion peak-top temperature of the purified salt of xcex2-hydroxyethoxy acetic acid employed is 205 to 208xc2x0 C.
[12] The process of manufacturing a purified 2-p-dioxanone as described in [10], characterized in that the fusion peak-top temperature of the purified salt of xcex2-hydroxyethoxy acetic acid employed is 206 to 207xc2x0 C.
[13] The process of manufacturing a purified 2-p-dioxanone as described in [10], characterized in that the fusion peak-top temperature of the purified salt of xcex2-hydroxyethoxy acetic acid employed is 206.5xc2x0 C.
[14] A purified 2-p-dioxanone obtained by the manufacturing process described in any one of [10] to
[15] The purified 2-p-dioxanone as described in [14], characterized in that the purified 2-p-dioxanone has a function to produce a polyparadioxane not having a carboxyl group at molecular ends after a polymerization reaction.
[16] The purified 2-p-dioxanone as described in [14], characterized in that the purified 2-p-dioxanone has a function to produce a polyparadioxane for which a peak at 8.1 ppm attributable to a proton of a carboxyl group by nuclear magnetic resonance spectrometry (NMR, measured at 25xc2x0 C.) is not detected after a polymerization reaction.
The advantages of the present invention are as follows:
(1) One of the advantages of the present invention is to provide a purified 2-p-dioxanone having a function to produce polyparadioxane having a high molecular weight and a narrow molecular weight distribution characterized by not having carboxyl group at molecular ends after a polymerization reaction.
(2) One of the advantages of the present invention is provide a purified 2-p-dioxanone having a function to produce polyparadioxane having a high molecular weight and a narrow molecular weight distribution characterized in that a peak at 8.1 ppm attributable to a proton of a carboxyl group by nuclear magnetic resonance spectrometry (NMR, measured at 25xc2x0 C.) is not detected after a polymerization reaction.
(3) One of the advantages of the present invention is to provide a purified salt of xcex2-hydroxyethoxy acetic acid, a precursor of a purified 2-p-dioxanone, which can readily be derived to the purified 2-p-dioxanone described in (1) and (2).
(4) One of the advantages of the present invention is to provide a process of manufacturing a purified salt of xcex2-hydroxyethoxy acetic acid, a precursor of a purified 2-p-dioxanone, which can readily be derived to the purified 2-p-dioxanone described in (1) and (2).
(5) One of the advantages of the present invention is to provide a purified salt of xcex2-hydroxyethoxy acetic acid, a precursor of a purified 2-p-dioxanone, which can readily be derived to the purified 2-p-dioxanone.
(6) One of the advantages of the present invention is to provide a process of manufacturing a purified salt of xcex2-hydroxyethoxy acetic acid, a precursor of a purified 2-p-dioxanone, which can readily be derived to the purified 2-p-dioxanone.
(7) One of the advantages of the present invention is to provide a process of manufacturing a purified 2-p-dioxanone from a purified salt of xcex2-hydroxyethoxy acetic acid.
(8) One of the advantages of the present invention is to provide a process of manufacturing a purified 2-p-dioxanone in an industrially advantageous manner.
(9) One of the advantages of the present invention is to provide technology for manufacturing a highly purified 2-p-dioxanone that is suitable as a raw material for polymers having a high molecular weight and narrow molecular weight distribution and contains less impurities at a high yield, considering the advantages of the prior art.
(10) One of the advantages of the present invention is to provide a purified 2-p-dioxanone, which can produce biodegradable absorbable polymers to be used for drugs and the like and polymers with a high molecular weight and narrow molecular weight distribution that can be extremely suitably used for sutures for surgical operations.